The present invention relates to a process for preparing mono-N-alkylated polyazamacrocycles.
T. A. Kaden, Top. Curr. Chem. 121, 157-75 (1984) has shown that simple alkylative techniques using electrophiles and polyazamacrocycles for the production of mono-N-functionalized polyazamacrocyles result in the formation of a mixture of mono, bis, and tris alkylated products which are difficult to separate and purify. To overcome this problem, large excesses of macrocycle, for example 5-10 equivalents relative to electrophile, have been employed by M. Studer et al., Helv. Chim. Acta. 69, 2081-86 (1986), by E. Kimura et al., J. Chem. Soc. Chem. Commun. 1158-59 (1986), and by Toyo Soda, (inventor:Kimura), J6 3014780-A (a published, but not yet examined, Japanese patent application). Additionally, auxiliary bases have used together with large excesses of macrocycle to obtain the mono-N-alkylation product by M. Studer et al., supra. Purification of the desired mono-N-alkylated product from the large excess of starting material and inorganic salt is a major problem associated with these methods. Additionally, the cost associated with employing a large excess of expensive reagent is prohibitive.
Other mono-N-alkylation attempts by F. Wagner et al., Inorg. Chem. 15, 408 (1976) involve selective deprotonation of a transition metal complex of a polyazamacrocycle with strong base followed by alkylation with methyl iodide. Further synthetic manipulation of this compound necessitates metal removal and purification which can be tedious.
Additional synthetic routes which afford mono-N-functional polyazamacrocycles involve lengthy, protection, functionalization, deprotection schemes which are divergent and not always general. For example, see P. S. Pallavincini et al., J. Amer. Chem. Soc. 109, 5139-44 (1987) and published European patent application 0 232 751 (1984).
In light of these limitations on mono-N-alkylation techniques existing in the art, it would be desirable to employ a direct alkylation approach which would not be reliant upon the use of excess macrocycle and an auxiliary base and yet would be selective for the desired mono-N-alkylated product.
Surprisingly, the present invention provides a process for preparing selectively the mono-N-alkylated products in a range of solvents without the use of large excesses of macrocycle and auxiliary base. The present process involves reacting between about one to five equivalents of a free base polyazamacrocycle with an appropriate electrophile in a solvent which will not promote a proton transfer.